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Introduction Synthetic clots are a critical tool for testing thrombectomy devices and for procedural training, offering high mechanical reproducibility through tunable stiffness and elasticity without the biohazard constraints of whole blood clots. Synthetic clots also enable complex in vitro testing setups without introducing biosafety risks, unlike human or animal clots. However, most synthetic clot models fail to capture a key clinically relevant behavior: fragmentation under shear forces during thrombectomy. Clot fragmentation is a major contributor to distal embolization and incomplete recanalization, making it a critical parameter for evaluating device safety and performance. Without this behavior, in vitro testing may underestimate failure modes and overestimate device efficacy. Prior work from the Bioengineering Devices Lab developed a physiologically relevant synthetic thrombus with replicable mechanical properties but limited fragmentation (doi:10.1136/jnis-2024-021743). To address this gap, this study aimed to engineer synthetic clots with reproducible mechanical properties that undergo controlled, shear-induced fragmentation, enabling more clinically representative device testing.Methods To replicate fragmentation behavior observed in human thrombi, controlled structural heterogeneities were introduced into synthetic clot analogs, including microspheres and other engineered discontinuities to act as internal stress concentrators. Mechanical properties were characterized using dynamic mechanical analysis (DMA rheometer; TA Instruments) to quantify viscoelastic behavior under physiologically relevant loading conditions. Fragmentation behavior was evaluated in a closed-loop flow system under controlled physiological pressures and flow rates. In select experiments, clot-device interaction was assessed using an aspiration catheter to evaluate fragmentation under thrombectomy-relevant conditions. Shear response was quantified by measuring resistance to deformation and downstream particulate generation, including fragment size distribution and fragmentation frequency, as a surrogate for distal embolization risk. Experimental results were compared to reference human clot datasets, and iterative design modifications were guided by reducing discrepancies in shear-dependent fragmentation behavior.Results Incorporation of controlled internal heterogeneities produced measurable changes in synthetic clot mechanical response under shear, resulting in increased susceptibility to fragmentation and particulate generation compared to homogeneous baseline models. Under aspiration catheter conditions, engineered clot analogs demonstrated increased shear-induced disruption and particulate generation compared to baseline constructs. Iterative refinement led to progressive alignment with human clot behavior, including enhanced shear responsiveness and a shift toward more clinically relevant fragment size distributions. These engineered clot analogs demonstrated early fragmentation behavior not observed in baseline constructs, indicating progression toward more physiologically representative failure modes.Conclusion Engineering internal heterogeneity within synthetic clots represents a promising strategy to better replicate the shear-dependent behavior of human thrombi. This iterative, data-driven approach improves the physiologic relevance of clot analogs and enhances the ability of in vitro models to capture clinically relevant failure modes, including fragmentation and distal embolization. These synthetic thrombi can be fabricated with consistent geometry and mechanical properties, enabling reproducible and scalable device testing. Future work will focus on further refining shear-dependent fragmentation behavior and incorporating imaging-compatible modifications, including radiopacity and particle image velocimetry (PIV), to enable detailed visualization of clot-device interactions.Disclosures K. Lewis: None. A. Wintermantel: None. E. Wilcox: None. C. Rapoport: None. S. Murza: None. W.E. Clark: None. T. Becker: None.